The long term objective of this proposal is to develop improved therapy for patients with colo-rectal cancer. The specific approach taken is to evaluate quinazoline analogs of folic acid synthesized by Dr. John Hynes, of the Medical University of South Carolina, as inhibitors of thymidylate synthetase per se or as components that enhance 5-fluorodeoxyuridylate binding to this enzyme. These compounds are also tested for activity vs the human colon carcinoma line HCT-8 and the rectal carcinoma line HCT-18, propagated in vitro. Promising compounds are then synthesized in larger quantity for more detailed studies, including effects on the growth of the colon adenocarcinoma #38 in mice. One compound (IAHQ) has been identified that has activity at low concentration vs the HCT-8 line as well as the murine colon carcinoma #38. Further studies of its mechanism of action are planned as well as pharmacologic studies in mice. Analogs will be tested that may have better antitumor properties. One of these compounds will be selected for possible clinical trial in patients with colorectal carcinoma, aided by in vitro stem cell assays of their tumor.